Pathomorphological Sequence of Nephron Loss in Diabetic Nephropathy

2021 ◽  
Author(s):  
Jana Löwen ◽  
Elisabeth Gröne ◽  
Marie-Luise Groß-Weißmann ◽  
Felix Bestvater ◽  
Hermann-Josef Gröne ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Basement Membrane ◽  
Interstitial Fibrosis ◽  
Glomerular Sclerosis ◽  
Structural Aberrations ◽  
Vascular Proliferation ◽  
Advanced Stages ◽  
Nephron Loss ◽  
Bowman's Capsule ◽  
Glomerular Capillaries

Abstract Following our reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN)(25,34) we now describe the advanced stages of DN terminating in glomerular obsolescence and tubulo-interstitial fibrosis based on a total of 918 biopsies. The structural aberrations emerge from two defects: First, an increased synthesis of glomerular basement membrane (GBM) components by podocytes and endothelial cells leading to an accumulation of GBM material in the mesangium. Second, a defect of glomerular vessels consisting of an increased leakiness and an increased propensity to proliferate. Both defects may lead to glomerular degeneration. The progressing compaction of the accumulated worn-out GBM-material together with the retraction of podocytes out of the tuft and the collapse and hyalinosis of capillaries results in a shrunken tuft that fuses with Bowman's capsule to glomerular sclerosis. The most frequent pathway to glomerular decay starts with local tuft expansions that result in contacts of structurally healthy podocytes to the parietal epithelium initiating the formation of tuft adhesions, which include the penetration of glomerular capillaries into BC. Exudation of plasma from such capillaries into the space between the parietal epithelium and its basement membrane causes the formation of insudative fluid accumulations within BC spreading around the glomerular circumference and, via the glomerulo-tubular junction, onto the tubule. Degeneration of the corresponding tubule develops secondarily to the glomerular damage, either due to cessation of filtration in cases of global sclerosis or due to encroachment of the insudative spaces. The degenerating tubules induce the proliferation of myo-fibroblasts resulting in interstitial fibrosis.

MO070NEW ASPECTS OF THE PATHOMORPHOLOGIC SEQUENCE OF NEPHRON LOSS IN DIABETIC NEPHROPATHY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Hermann Gröne ◽  
Wilhelm Kriz ◽  
Jana Loewen ◽  
Elisabeth Groene
Keyword(s):  
Diabetic Nephropathy ◽  
Basement Membrane ◽  
Mesangial Cells ◽  
Capillary Endothelium ◽  
Tubular Damage ◽  
Mesangial Matrix ◽  
Nephron Loss ◽  
Bowman's Capsule ◽  
Glomerular Damage ◽  
Glomerular Capillaries

Abstract Background and Aims Diabetic nephropathy (DN) is the leading cause of end-stage-renal disease in western countries. Despite of innumerable studies undertaken to elucidate the pathogenesis of DN the underlying morphologic alterations have been insufficiently analyzed. Method Re-evaluation of more than 800 biopsies was done showing several unknown features. Results: 1. Matrix accumulation in the mesangium: Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of DN, generally considered to emerge from different sites of overproduction: GBM components from podocytes and mesangial matrix from mesangial cells. We show, that the accumulation of matrix in the mesangium emerges from an overproduction of GBM material by podocytes and endothelial cells and an impaired degradation by mesangial cells. The progressing deposition of worn-out GBM material into the mesangium accounts for the advancement from diffuse mesangial sclerosis (DMS) to nodular sclerosis (NS) and to the herniation of the tuft through the glomerular vascular pole to the outside; the latter is associated with the outgrowth of glomerular capillaries into the peri-glomerular space leading to the destruction of the juxtaglomerular apparatus. 2.The role of podocytes Podocytes have frequently been accused to play a central role in DN. This is correct, but in another way than generally assumed. Damage to podocytes cannot be seen in DMS. The albuminuria regularly seen during this stage derives, as previously suggested by others, from an increased leakiness of the glomerular capillary endothelium based on a deranged glycocalyx. Podocyte detachments start at the transition from DMS to NS, based on the loss of cross talk signals with the capillary endothelium: the increasing deposition of matrix leads to the collapse of many capillaries. These podocytes contribute little to the further progression of the damage: they are lost into primary urine or they undergo cell lysis.In addition to their role in increased matrix production, podocytes take an active role in the formation of tuft adhesions to Bowman’s capsule (BC), starting the progression to NS. Expansion of the matrix within the mesangium has led to expansion of the tuft (frequently associated with nodules) towards Bowman’s capsule (BC) or towards the urinary orifice. Podocytes on the surface of these expansions are in their majority structurally intact, exhibiting an intact pattern of foot processes. These podocytes come into contact with parietal epithelial cells and initiate DN-specific tuft adhesions to BC allowing the proliferation of glomerular capillaries into BC. There they deliver an exudate into BC that spreads around the entire circumference of the glomerulus presenting as giant insudative spaces. Moreover, this process encroaches via the glomerulo-tubular junction onto the tubule constituting the major pathway of glomerular damage extending to the tubulointerstitium. 3. Tubulointerstitial fibrosisIt is current opinion that the tubulointerstitial fibrosis may start from tubular damage resulting in an own, glomerular-independent pathway to nephron loss. However, there is scant evidence for such a mechanism. Studying 162 glomerulo-tubular transitions, we did not see a tubular epithelial or interstitial damage in those biopsies without any evidence of a glomerulo-tubular damage transfer. The only exception consists of the well-known prominent thickening of the tubular basement membrane, which may result in functional loss but does not lead to structural epithelial damage. Conclusion We consistently found that tubulo-interstitial damage develops after encroachment of the glomerular damage onto the tubule, leading first to a gradual degeneration of tubules which subsequently initiate the process of interstitial fibrosis.

Increased urinary miR-196a level predicts the progression of renal injury in patients with diabetic nephropathy

2018 ◽  
Vol 35 (6) ◽  
pp. 1009-1016 ◽  
Author(s):  
Yu An ◽  
Changming Zhang ◽  
Feng Xu ◽  
Wei Li ◽  
Caihong Zeng ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Cox Regression ◽  
Interstitial Fibrosis ◽  
Glomerular Sclerosis ◽  
Tubular Atrophy ◽  
Cox Regression Analysis ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background Recent data suggest that miR-196a is predominantly expressed in the kidney and plays an inhibitory role in the progress of renal interstitial fibrosis (IF). However, the predictive value of miR-196a in diabetic nephropathy (DN) remains unknown. We validated the role of urinary miR-196a in the progression of renal injury in a cohort of patients with type 2 diabetes mellitus. Methods Our study included 209 patients with biopsy-proven DN. The mean follow-up time was 54.03 ± 32.94 months. Histological lesions were assessed using the pathological classification established by the Renal Pathology Society. Percentages of IF and tubular atrophy were assessed using the Aperio ScanScope system. We measured the correlation of urinary miR-196a with clinical and pathological parameters using the Spearman’s correlation test. The influence of urinary miR-196a on renal outcomes was assessed using Cox regression analysis. Results Urinary miR-196a levels correlated positively with proteinuria (ρ = 0.385, P < 0.001), duration of diabetes mellitus (ρ = 0.255, P < 0.001) and systolic blood pressure (ρ = 0.267, P < 0.001). The baseline estimated glomerular filtration rate (eGFR) and hemoglobin level showed a negative correlation with urinary miR-196a (ρ = −0.247, P < 0.001 and ρ = −0.236, P = 0.001, respectively). Pathologically, urinary miR-196a levels correlated with glomerular sclerosis and IF in patients with DN. Urinary miR-196a was significantly associated with progression to end-stage renal disease [hazard ratio (HR) 2.03, P < 0.001] and a 40% reduction of baseline eGFR (HR 1.75, P = 0.001), independent of age, gender, body mass index, mean arterial pressure and hemoglobinA1c level. However, urinary miR-196a did not improve predictive power to proteinuria and eGFR in DN patients. Conclusions Increased urinary miR-196a was significantly associated with the progression of renal injury and might be a noninvasive prognostic marker of renal fibrosis in DN patients.

scholarly journals Bioinformatic Evaluation of Transcriptional Regulation of WNT Pathway Genes with reference to Diabetic Nephropathy

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Gareth J. McKay ◽  
David H. Kavanagh ◽  
John K. Crean ◽  
Alexander P. Maxwell
Keyword(s):  
Transcription Factor ◽  
Diabetic Nephropathy ◽  
Wnt Pathway ◽  
Interstitial Fibrosis ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Gene Promoter ◽  
Therapeutic Benefit ◽  
Fold Change ◽  
Glomerular Sclerosis

Objective.WNT/β-catenin pathway members have been implicated in interstitial fibrosis and glomerular sclerosis disease processes characteristic of diabetic nephropathy (DN), processes partly controlled by transcription factors (TFs) that bind to gene promoter regions attenuating regulation. We sought to identify predictedcis-acting transcription factor binding sites (TFBSs) overrepresented within WNT pathway members.Methods.We assessed 62 TFBS motif frequencies from the JASPAR databases in 65 WNT pathway genes.Pvalues were estimated on the hypergeometric distribution for each TF. Gene expression profiles of enriched motifs were examined in DN-related datasets to assess clinical significance.Results.Transcription factor AP-2 alpha (TFAP2A), myeloid zinc finger 1 (MZF1), and specificity protein 1 (SP1) were significantly enriched within WNT pathway genes (Pvalues < 6.83 × 10−29, 1.34 × 10−11, and 3.01 × 10−6, resp.).MZF1expression was significantly increased in DN in a whole kidney dataset (fold change = 1.16; 16% increase;P=0.03).TFAP2Aexpression was decreased in an independent dataset (fold change = −1.02;P=0.03). No differential expression ofSP1was detected.Conclusions.Three TFBS profiles are significantly enriched within WNT pathway genes highlighting the potential ofin silicoanalyses for identification of pathway regulators. Modification of TF binding may possibly limit DN progression, offering potential therapeutic benefit.

scholarly journals Multi-Omics Analysis of Diabetic Nephropathy Reveals Potential New Mechanisms and Drug Targets

2020 ◽  
Vol 11 ◽  
Author(s):  
Qian Sha ◽  
Jinxiu Lyu ◽  
Meng Zhao ◽  
Haijuan Li ◽  
Mengzhe Guo ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Interstitial Fibrosis ◽  
Stearidonic Acid ◽  
Fatty Acyl ◽  
Glomerular Sclerosis ◽  
Transporter Protein ◽  
Stage Renal Disease

Diabetic nephropathy (DN) is one of the most common diabetic complications, which is the major course of end-stage renal disease (ESRD). However, the systematical molecular characterizations during DN pathogenesis and progression has not been not well understood. To identify the fundamental mediators of the pathogenesis and progression of DN. we performed a combination RNASeq, proteomics, and metabolomics analyses of both patients’ derived kidney biopsy samples and kidneys from in vivo DN model. As a result, molecular changes of DN contain extracellular matrix accumulation, abnormal activated inflamed microenvironment, and metabolism disorders, bringing about glomerular sclerosis and tubular interstitial fibrosis. Specificity, Further integration analyses have identified that the linoleic acid metabolism and fatty-acids β-oxidation are significantly inhibited during DN pathogenesis and progression, the transporter protein ABCD3, the fatty acyl-CoA activated enzymes ACOX1, ACOX2, and ACOX3, and some corresponding metabolites such as 13′-HODE, stearidonic acid, docosahexaenoic acid, (±)10(11)-EpDPA were also significantly reduced. Our study thus provides potential molecular mechanisms for DN progression and suggests that targeting the key enzymes or supplying some lipids may be a promising avenue in the treatment of DN, especially advanced-stage DN.

scholarly journals Protective Effects of Chromium Picolinate Against Diabetic-Induced Renal Dysfunction and Renal Fibrosis in Streptozotocin-Induced Diabetic Rats

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 398 ◽  
Author(s):  
Shan Shan Qi ◽  
Hong Xing Zheng ◽  
Hai Jiang ◽  
Li Ping Yuan ◽  
Le Chen Dong
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Biological Activities ◽  
Serum Insulin ◽  
Treated Group ◽  
Chromium Picolinate ◽  
Glomerular Sclerosis ◽  
Protective Effects ◽  
Tgf Β1

Diabetic nephropathy (DN) is one of the most important complications of diabetes, and the leading cause of end-stage renal disease (ESRD). While Chromium picolinate (CrPic) supplementation has been found to be effective in treating diabetes, its effects on diabetic-induced nephropathy have not been studied. Therefore, in this study, CrPic (1 mg kg−1 d−1) was administered to a DN rat model by oral gavage for eight weeks to investigate its effects. The results show that CrPic supplementation caused a decrease in levels of blood glucose, serum insulin, blood urea nitrogen (BUN), serum creatinine, and urinary albumin in DN rats. It also reversed renal pathological changes, including renal glomerular sclerosis and interstitial fibrosis. In addition, the oxidative defense system in the kidneys of DN rats was found to be improved; the biological activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) increased; and the content of malondialdehyde (MDA) lowered. Immunohistochemical results reveal that the expression levels of renal transforming growth factor-β1 (TGF-β1), Smad 2, and Smad 3 decreased significantly in the kidneys of rats in the CrPic-treated group. CrPic administration was thus found to ameliorate diabetic nephropathy in SD rats via an antioxidative stress mechanism, as well the ability to inhibit TGF-β1/Smad2/3 expression. This study suggests that CrPic could be a potential renal-protective nutrient against diabetic nephropathy.

scholarly journals Osteopontin Plays a Critical Role in Interstitial Fibrosis but Not Glomerular Sclerosis in Diabetic Nephropathy

Nephron Extra ◽  
2012 ◽  
Vol 2 (1) ◽  
pp. 87-103 ◽  
Author(s):  
Tomoaki Nagao ◽  
Takafumi Okura ◽  
Jun Irita ◽  
Masanori Jotoku ◽  
Daijiro Enomoto ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Glomerular Sclerosis

scholarly journals Effect of spironolactone on diabetic nephropathy in albino rats: ultrastructural and immunohistochemical study

2017 ◽  
Vol 3 (5) ◽  
pp. 110
Author(s):  
Hassan M. Rezk ◽  
Mohamed El-Sherbiny ◽  
Hoda Atef ◽  
Medhat Taha ◽  
Samar Hamdy ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Basement Membrane ◽  
Interstitial Fibrosis ◽  
Diabetic Rats ◽  
Ultrastructural Changes ◽  
Control Group ◽  
Albino Rats ◽  
Electron Microscopic ◽  
Group V ◽  
Group I

<p class="abstract"><strong>Background:</strong> Diabetic nephropathy (DN) has become one of the most common causes of end stage renal disease (ESRD). Hyperglycemia induces oxidative stress in renal tubular epithelial cells that initiate tubulointerstitial fibrosis, which is a characteristic feature of diabetic nephropathy that becomes progressively complicated by renal failure. Aim: To assess the effect of spironolactone (SPL) on WT-1 protein expression and ultrastructural changes associated with the progression of experimental diabetic nephropathy (DN).</p><p class="abstract"><strong>Methods:</strong> Forty female albino rats were divided into five groups. Group I (control group), Group II (untreated diabetic rats), Group III (insulin-treated diabetic rats), Group IV (spironolactone-treated diabetic rats) and Group V (insulin and spironolactone-treated diabetic rats). At the 4<sup>th</sup> and 8<sup>th</sup> weeks, 4 rats from each group were sacrificed and renal tissue and blood samples were obtained. The rats were anaesthetized using ether inhalation. Each kidney was longitudinally divided and processed for immunohistochemical analysis with rabbit polyclonal anti-WT-1 Antibody and electron microscopic examination.</p><p class="abstract"><strong>Results:</strong> Treatment of STZ-induced diabetic rats with insulin and spironolactone (Group V) showed improvement in renal corpuscles as well as their capsular space, the basement membrane became normal with preserved minor and major processes and subpodocytic space, most of the proximal convoluted tubules retained their brush border, and their cells showed normal euchromatic nuclei and scattered mitochondria with apical microvilli, which is similar to the findings of the control group. Quantitative analyses showed significant increase in area of fibrosis and focal thickening of the glomerular basement membrane in non-SPL treated groups. There was a marked decrease in proteinuria compared to other treated groups. The results were better after 8 weeks compared to those after 4 weeks.</p><strong>Conclusions:</strong> The administration of SPL significantly prevented the extent of interstitial fibrosis in the diabetic kidney.

scholarly journals Protective Effects of Ethanolic Extract from Rhizome of Polygoni avicularis against Renal Fibrosis and Inflammation in a Diabetic Nephropathy Model

2021 ◽  
Vol 22 (13) ◽  
pp. 7230
Author(s):  
Jung-Joo Yoon ◽  
Ji-Hun Park ◽  
Yun-Jung Lee ◽  
Hye-Yoom Kim ◽  
Byung-Hyuk Han ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Diabetic Nephropathy ◽  
Renal Dysfunction ◽  
Renal Fibrosis ◽  
Mesangial Cells ◽  
Resistance Index ◽  
Ethanolic Extract ◽  
Glomerular Sclerosis ◽  
Oral Glucose ◽  
Inflammatory Factor

Progressive diabetic nephropathy (DN) in diabetes leads to major morbidity and mortality. The major pathological alterations of DN include mesangial expansion, extracellular matrix alterations, tubulointerstitial fibrosis, and glomerular sclerosis. Polygoni avicularis is widely used in traditional oriental medicine and has long been used as a diuretic, astringent, insecticide and antihypertensive. However, to the best of the authors’ knowledge, the effects of the ethanolic extract from rhizome of Polygoni avicularis (ER-PA) on DN have not yet been assessed. The present study aimed to identify the effect of ER-PA on renal dysfunction, which has been implicated in DN in human renal mesangial cells and db/db mice and investigate its mechanism of action. The in vivo experiment was performed using Polygoni avicularis-ethanol soluble fraction (ER-PA) and was administrated to db/db mice at 10 and 50 mg/kg dose. For the in vitro experiments, the human renal mesangial cells were induced by high glucose (HG, 25 mM). The ER-PA group showed significant amelioration in oral glucose tolerance, and insulin resistance index. ER-PA significantly improved the albumin excretion and markedly reduced plasma creatinine, kidney injury molecule-1 and C-reactive protein. In addition, ER-PA significantly suppressed inflammatory cytokines. Histopathologically, ER-PA attenuated glomerular expansion and tubular fibrosis in db/db mice. Furthermore, ER-PA suppressed the expression of renal fibrosis biomarkers (TGF and Collagen IV). ER-PA also reduced the NLR family pyrin domain containing 3 inflammatory factor level. These results suggest that ER-PA has a protective effect against renal dysfunction through improved insulin resistance as well as the inhibition of nephritis and fibrosis in DN.

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